The invention relates generally to non-invasively imaging a preselect portion of the lower abdomen and groin area of a patient with X-rays, at relatively lower radiation dosages than currently used in, and improved resolution than currently achievable with, conventional Computed Tomography (CT) scanning.
Various physiological changes can occur in the lower abdomen region of a patient requiring diagnostic and imaging approaches to aid medical personnel in diagnosing, prognosticating, and managing or otherwise treating these changes.
For example, as described in U.S. Pat. No. 6,171,796 (An, et al.) entitled Biomarkers and Targets for Diagnosis Prognosis and Management of Prostate Disease, carcinoma of the prostate (PCA) is the second-most frequent cause of cancer related death in men in the United States (citing Boring et al., CA-Cancer J. Pract., 43:7-26, 1993; and Wingo et. al., CA Cancer J. Clin., 47(4):239-242, 1997). The increased incidence of prostate cancer during the 1980s has established prostate cancer as the most prevalent of all cancers (citing Carter and Coffey, Prostate, 16:39-48, 1990). Although prostate cancer is the most common cancer found in United States men, (approximately 210,000 newly diagnosed cases/year), the molecular changes underlying its genesis and progression remain poorly understood (citing Boring et al., CA-Cancer J. Pract., 43:7-26, 1993). According to American Cancer Society estimates, the number of deaths from PCA is increasing in excess of 8% annually.
An unusual challenge presented by prostate cancer is that most prostate tumors do not represent life threatening conditions. Evidence from autopsies indicate that an estimated 11 million American men have prostate cancer (citing Dbom, Cancer Res. Clin. Oncol., 106:210-218, 1983). These figures are consistent with prostate carcinoma having a protracted natural history in which relatively few tumors progress to clinical significance during the lifetime of the patient. If the cancer is well-differentiated, organ-confined and focal when detected, treatment does not extend the life expectancy of older patients.
Unfortunately, the relatively few prostate carcinomas that are progressive in nature are likely to have already metastasized by the time of clinical detection. Survival rates for individuals with metastatic prostate cancer are quite low. Between these two extremes are patients with prostate tumors that will metastasize but have not yet done so. For these patients, surgical removal of their prostates is curative and extends their life expectancy. Therefore, early detection and determination of which group a newly diagnosed patient falls within is critical in determining optimal treatment and patient survival.
The most commonly utilized current tests for prostate cancer are digital rectal examination (DRE) and analysis of serum prostate specific antigen (PSA). Although PSA has been widely used as a clinical marker of prostate cancer since 1988 (citing Partin and Oesterling, J. Urol., 152:1358-1368, 1994), screening programs utilizing PSA alone or in combination with digital rectal examination have not been successful in improving the survival rate for men with prostate cancer (citing Partin and Oesterling, J. Urol., 152:1358-1368, 1994). While PSA is specific to prostate tissue, it is produced by normal and benign as well as malignant prostatic epithelium, resulting in a high false-positive rate for prostate cancer detection (citing Partin and Oesterling, J. Urol., 152:1358-1368, 1994).
Other markers that have been used for prostate cancer detection include prostatic acid phosphatase (PAP) and prostate secreted protein (PSP). PAP is secreted by prostate cells under hormonal control (citing Partin and Oesterling, J. Urol., 152:1358-1368, 1994). It has less specificity and sensitivity than does PSA. As a result, it is used much less now, although PAP may still have some applications for monitoring metastatic patients that have failed primary treatments. In general, PSP is a more sensitive biomarker than PAP, but is not as sensitive as PSA (citing Huang et al., Prostate, 23: 201-212, 1993). Like PSA, PSP levels are frequently elevated in patients with benign prostatic hypertrophy or hyperplasia (BPH) as well as those with prostate cancer.
Another serum marker associated with prostate disease is prostate specific membrane antigen (PSMA) (citing Horoszewicz et al., Anticancer Res., 7:927-936, 1987; Carter et al., Proc. Nat'l Acad. Sci. USA 93: 749-753, 1996; and Murphy et al., Cancer, 78: 809-818, 1996). PSMA is a Type II cell membrane protein and has been identified as Folic Acid Hydrolase (FAH) (Carter et al., Proc. Nat'l Acad. Sci. USA 93: 749-753, 1996). Antibodies against PSMA react with both normal prostate tissue and prostate cancer tissue (citing Horoszewicz et al., Anticancer Res., 7:927-936, 1987). In the cited Murphy et al. publication (Prostate, 26:164-168, 1995) Murphy et al. used ELISA to detect serum PSMA in advanced prostate cancer. As a serum test, PSMA levels are a relatively poor indicator of prostate cancer. However, PSMA may have utility in certain circumstances. PSMA is expressed in metastatic prostate tumor capillary beds (citing Silver et al., Clin. Cancer Res., 3: 81-85, 1997) and is reported to be more abundant in the blood of metastatic cancer patients (citing Murphy et al., Cancer, 78: 809-818, 1996). PSMA messenger RNA (mRNA) is down-regulated 8-10 fold in the LNCAP prostate cancer cell line after exposure to 5-.alpha.-dihydroxytestosterone (DHT) (citing Israeli et al., Cancer Research, 54:1807-1811, 1994).
A relatively new potential biomarker for prostate cancer is human kallekrein 2 (HK2) (citing Piironen et al., Clin. Chem. 42: 1034-1041, 1996). HK2 is a member of the kallekrein family that is secreted by the prostate gland. In theory, serum concentrations of HK2 may be of utility in prostate cancer detection or diagnosis, but the usefulness of this marker is still being evaluated.
U.S. Pat. Nos. 6,171,796 (An, et al.) and 6,090,559 (Russell, et al.) describe other biomarkers and targets for diagnosis prognosis and management of prostate disease.
As described in U.S. Pat. No. 6,136,311 (Bander), at the time of clinical diagnosis, as many as 25% of patients have bone metastasis demonstrable by radionuclide scans. Murphy, G. P., et al., “The National Survey Of Prostate Cancer In The United States By The American College Of Surgeons,” J. Urol., 127:928-939 (1982). Accurate clinical evaluation of nodal involvement has proven to be difficult. Currently available imaging techniques such as computed tomography (“CT”) or magnetic resonance imaging (“MRI”) are unable to distinguish metastatic prostate cancer involvement of lymph nodes by criterion other than size. More specifically, current conventional, high resolution, CT scanners provide pixelated images limited to about 15 to 20 line pairs/cm, corresponding to imaged areas of about 500 to 1000 microns/pixel. Therefore, by definition, to date these imaging modalities are inherently insensitive in the detection of small volume (<500-1000 microns) disease as well as non-specific in the detection of larger volume adenopathy. A recent study assessed the accuracy of MRI in patients with clinically localized prostate cancer. Rifkin et al., “Comparison Of Magnetic Resonance Imaging And Ultrasonography In Staging Early Prostate Cancer,” N. Engel. J. Med., 323:621-626 (1990). In this study, 194 patients underwent a MRI and 185 of these patients had a lymph node dissection. 23 (13%) patients had pathologically involved lymph nodes. MRI was suspicious in only 1 of these 23 cases resulting in a sensitivity of 4%. Similar results have also been noted with conventional CT scans. Gasser et al., “MRI And Ultrasonography In Staging Prostate Cancer,” N. Engl. J. Med. (Correspondence), 324(7):49-495 (1991).
While resolution is a key drawback with current imaging techniques, current CT scanners require a gantry supporting the x-ray source and detectors to rotate around the patient, and in particular his hips and pelvic bones, requiring radiation at levels sufficient to transmit through dense bone in order to acquire adequate information to image the prostate and its soft tissue environs.
One diagnostic tool that has proved helpful in the detection of diseased tissue in the body is referred to as in vivo imaging. The term “in vivo imaging” refers to any method which permits the detection or measurement of a biological process using an imaging modality. It is usually accomplished in connection with cancer cells by using a biological agent administered to a patient, the agent being of the type that is localized to the tumor bearing the antigen with which the biological agent reacts, and is detected or “imaged” using an appropriate imaging modality. The prior art in vivo imaging modalities include known techniques such as radionuclear scanning using e.g., a gamma camera or emission tomography. See e.g., A. R. Bradwell et al., “Developments in Antibody Imaging”, Monoclonal Antibodies for Cancer Detection and Therapy, R. W. Baldwin et al., (eds.), pp. 65-85 (Academic Press 1985), which is hereby incorporated by reference. Alternatively, a positron emission transaxial tomography (PET) scanner has been used where the radiolabel is a constrast agent that emits positrons. A more general discussion of molecular imaging is described in Weissleder, et al., “Molecular Imaging”, Radiology, (Vol. 219, No. 2), May 2001, pp 316-333.